Publication
Discovery of novel mechanisms of centrosome amplification and their therapeutic value in cancer
| datacite.subject.fos | Ciências Médicas::Ciências da Saúde | pt_PT |
| dc.contributor.advisor | Maia, Ana Teresa | |
| dc.contributor.advisor | Morais, Nuno Barbosa | |
| dc.contributor.author | Almeida, Bernardo Lucas Carvalho Pereira de | |
| dc.date.accessioned | 2018-06-21T13:44:20Z | |
| dc.date.available | 2020-12-04T01:30:19Z | |
| dc.date.issued | 2017-12-04 | |
| dc.date.submitted | 2017 | |
| dc.description.abstract | Genomic instability is a hallmark of cancer cells that generates the genetic diversity that makes possible the acquisition of all the other hallmarks. Thus, the maintenance of genome stability is critical for proper cell function. Centrosomes, the major microtubule-organising centres of animal cells, are the main subcellular organelles implicated in the maintenance of genome stability. It is therefore not surprising that centrosome amplification (CA) – the presence of more than one centrosome in a cell – is a common feature in cancer. Recent work from the Bettencourt-Dias Lab has identified a new recurrent feature of cancer cells: centriole over-elongation (COE), which also promotes CA. Those abnormalities are specific features of cancer cells and hence appealing targets in cancer therapy. However, their origins and therapeutic value remain poorly understood, preventing their use in the clinic. We have screened the NCI-60 panel of human cancer cell lines for centriole number and individual length to test their frequency and interdependence. We have thereby also generated a metric capturing each abnormality level per cell line that we then correlated with the publicly available molecular (particularly transcriptomic and proteomic) and drug-sensitivity quantitative profiles for that panel. Our work showed lower frequency of COE compared to CA and lung and skin as the primary cancer tissues with higher centriole length heterogeneity. However, the two features are not independent, with overly-longer centrioles being more common in cells with CA. Our single-cell analyses have also suggested that cells apparently do not control their overall centriolar mass when the centriole number increases. Moreover, cancer cell lines with longer centrioles proliferated slower due to an accumulation of cells in G1 phase, suggesting that centriole length defects could lead to a cell cycle delay in G1. In addition, our original genomewide approach highlighted putative mechanisms associated with both abnormalities in cancer, such as the PRKACA kinase promoting COE and the proteasome protecting cells from CA. Correlation with drug activity have both associated CA with higher sensitivity to compound activity and also identified some compounds as potential therapeutic options to selectively target cells with higher incidence of centriole abnormalities. This work provides the first single-centriole-level portrait of centriole abnormalities in cancer and contributes to the understanding of their molecular origins, namely by revealing novel molecular mechanisms in cell cycle biology. Given the cancer-specificity of these abnormalities, the identified compounds will inspire the development of clinical applications based on selectively targeting these Achilles’ heels of cancer cells. | |
| dc.identifier.tid | 201930641 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.1/10701 | |
| dc.language.iso | eng | pt_PT |
| dc.subject | Cancro | pt_PT |
| dc.subject | Instabilidade genómica | pt_PT |
| dc.subject | Painel NCI-60 | pt_PT |
| dc.subject | Amplificação centrossomal | pt_PT |
| dc.subject | Sobre-elongação centriolar | pt_PT |
| dc.subject | Terapias direcionadas | pt_PT |
| dc.title | Discovery of novel mechanisms of centrosome amplification and their therapeutic value in cancer | pt_PT |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| person.familyName | Almeida | |
| person.givenName | Bernardo | |
| person.identifier.orcid | 0000-0002-6084-6775 | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | masterThesis | pt_PT |
| relation.isAuthorOfPublication | a20b550d-d54a-46ae-9e17-3eb5fa5409cc | |
| relation.isAuthorOfPublication.latestForDiscovery | a20b550d-d54a-46ae-9e17-3eb5fa5409cc | |
| thesis.degree.grantor | Universidade do Algarve. Departamento de Ciências Biomédicas e Medicina | |
| thesis.degree.level | Mestre | |
| thesis.degree.name | Mestrado em Oncobiologia - Mecanismos Moleculares do Cancro | pt_PT |